A Proteomic Approach Identifies Isoform-Specific and Nucleotide-Dependent RAS Interactions.

Molecular & cellular proteomics : MCP Pub Date : 2022-08-01 Epub Date: 2022-07-14 DOI:10.1016/j.mcpro.2022.100268
Seth P Miller, George Maio, Xiaoyu Zhang, Felix S Badillo Soto, Julia Zhu, Stephen Z Ramirez, Hening Lin
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引用次数: 3

Abstract

Active mutations in the RAS genes are found in ∼30% of human cancers. Although thought to have overlapping functions, RAS isoforms show preferential activation in human tumors, which prompted us to employ a comparative and quantitative proteomics approach to generate isoform-specific and nucleotide-dependent interactomes of the four RAS isoforms, KRAS4A, KRAS4B, HRAS, and NRAS. Many isoform-specific interacting proteins were identified, including HRAS-specific CARM1 and CHK1 and KRAS-specific PIP4K2C and IPO7. Comparing the interactomes of WT and constitutively active G12D mutant of RAS isoforms, we identified several potential previously unknown effector proteins of RAS, one of which was recently reported while this article was in preparation, RADIL. These interacting proteins play important roles as knockdown or pharmacological inhibition leads to potent inhibition of cancer cells. The HRAS-specific interacting protein CARM1 plays a role in HRAS-induced senescence, with CARM1 knockdown or inhibition selectively increasing senescence in HRAS-transformed cells but not in KRAS4B-transformed cells. By revealing new isoform-specific and nucleotide-dependent RAS interactors, the study here provides insights to help understand the overlapping functions of the RAS isoforms.

Abstract Image

Abstract Image

Abstract Image

蛋白质组学方法鉴定异构体特异性和核苷酸依赖的RAS相互作用。
在约30%的人类癌症中发现了RAS基因的活跃突变。虽然被认为具有重叠的功能,但RAS亚型在人类肿瘤中表现出优先激活,这促使我们采用比较和定量的蛋白质组学方法来生成四种RAS亚型,KRAS4A, KRAS4B, HRAS和NRAS的亚型特异性和核苷酸依赖性相互作用组。许多异构体特异性相互作用蛋白被鉴定出来,包括hras特异性CARM1和CHK1以及kras特异性PIP4K2C和ip7。通过比较RAS亚型的WT和组成型活性G12D突变体的相互作用组,我们发现了几个潜在的以前未知的RAS效应蛋白,其中一个是最近报道的,而这篇文章正在准备中。这些相互作用的蛋白在敲除或药理抑制导致对癌细胞的有效抑制方面发挥着重要作用。hras特异性相互作用蛋白CARM1在hras诱导的衰老中发挥作用,CARM1敲低或抑制选择性地增加了hras转化细胞的衰老,而在kras4b转化细胞中则没有。通过揭示新的异构体特异性和核苷酸依赖性的RAS相互作用因子,本研究提供了有助于理解RAS异构体重叠功能的见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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